Abstract
Diabetes mellitus induces a reduction in skeletal muscle mass and strength. Strength training is prescribed as part of treatment since it improves glycemic control and promotes increase of skeletal muscle mass. The mechanisms involved in overload-induced muscle hypertrophy elicited at the establishment of the type I diabetic state was investigated in Wistar rats. The purpose was to examine whether the overload-induced hypertrophy can counteract the hypotrophy associated to the diabetic state. The experiments were performed in oxidative (soleus) or glycolytic (EDL) muscles. PI3K/Akt/mTOR protein synthesis pathway was evaluated 7 days after overload-induced hypertrophy of soleus and of EDL muscles. The mRNA expression of genes associated with different signaling pathways that control muscle hypertrophy was also evaluated: mechanotransduction (FAK), Wnt/β-catenin, myostatin, and follistatin. The soleus and EDL muscles when submitted to overload had similar hypertrophic responses in control and diabetic animals. The increase of absolute and specific twitch and tetanic forces had the same magnitude as muscle hypertrophic response. Hypertrophy of the EDL muscle from diabetic animals mostly involved mechanical loading-stimulated PI3K/Akt/mTOR pathway besides the reduced activation of AMP-activated protein kinase (AMPK) and decrease of myostatin expression. Hypertrophy was more pronounced in the soleus muscle of diabetic animals due to a more potent activation of rpS6 and increased mRNA expression of insulin-like growth factor-1 (IGF-1), mechano-growth factor (MGF) and follistatin, and decrease of myostatin, MuRF-1 and atrogin-1 contents. The signaling changes enabled the soleus muscle mass and force of the diabetic rats to reach the values of the control group.
Highlights
Reduced protein synthesis stimulation and increased protein degradation (Sandri, 2008; Schiaffino et al, 2013) are associated with the loss of skeletal muscle mass in type 1 diabetes (Barazzoni et al, 2004)
We examined and compared the effects of short-term diabetic condition associated with a state of intense skeletal muscle stimulus for hypertrophy induced by overload on signaling pathways associated with protein synthesis and degradation controlled by phosphoinositide 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR), including the E3 ubiquitin ligase that are increased in atrophic conditions, MuRF1 and atrogin-1; mechanotransduction by ribosomal protein S6 (rpS6) phosphorylation and mRNA expression of Focal Adhesion Kinase (FAK) and mechano-growth factor (MGF); mRNA expressions of myostatin and follistatin, Wnt/βcatenin and MG53 that are involved in myogenesis and may affect insulin signaling (Jung and Ko, 2010; Lee et al, 2010)
In the extensor digitorum longus (EDL) muscle of control animals, there was an increase of 25% in both absolute and normalized muscle wet weight due to the overload
Summary
Reduced protein synthesis stimulation and increased protein degradation (Sandri, 2008; Schiaffino et al, 2013) are associated with the loss of skeletal muscle mass in type 1 diabetes (Barazzoni et al, 2004). Animals with diabetes mellitus induced by streptozotocin administration have increased short-term proteolytic activity in the skeletal muscle (1–3 days after diabetes induction) that returns to control values after 5–10 days (Pepato et al, 1996). Streptozotocin-induced diabetic animals exhibit increased AMP kinase (AMPK) phosphorylation (Vitzel et al, 2013b) and impairs muscle hypertrophy through a reduced activation of protein synthesis signaling such as protein kinase B (Akt) in Ser473, mammalian target of rapamycin (mTOR) in Ser2448, ribosomal protein S6 (rpS6) in Thr389, and 4E binding protein (4EBP-1) in Thr (Bolster et al, 2002; Thomson and Gordon, 2005). Little is known about the association of diabetes mellitus and the skeletal muscle mass hypertrophy induced by resistive physical exercise. After 30 days of hypertrophic stimulus, the skeletal muscle mass increase reaches a plateau (Armstrong and Ianuzzo, 1977; Farrell et al, 1999; Katta et al, 2010)
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